Dominantly acting proto-oncogenes and organizers of tissue polarity, such as the NF-kappaB/Rel and Hedgehog family proteins, control cellular growth via terminal downstream targets that are as yet largely unidentified. NF-kappaB and Sonic Hedgehog (SHH) exert profound but opposite effects on epidermal growth and may play significant roles in human skin disease. A role for NF-kappaB proteins in controlling epidermal growth has recently been identified by the principal investigator. SHH pathway activation in human basal cell carcinoma has also recently been demonstrated by a key collaborator on this proposal and recently confirmed by the principal investigator in studies with engineered human epidermis in vivo. These findings have led us to propose the following hypothesis: NF-kappaB helps trigger the growth arrest associated with terminal differentiation of suprabasal epidermis while SHH can promote a proliferative expansion of basal epithelium. We suggest that understanding the mode of action of these 2 dominant regulators may lead to fundamental insights into epithelial insights into epithelial biology and new therapeutic targets for clinical disorders of abnormal epidermal proliferation. The overall goal of this proposal is to define mechanisms of NF-kappaB and SHH action in epidermal growth regulation. First, we plan to characterize the genes downstream of NF-kappaB and SHH activation in epidermis. To do this, we will examine the impact of NF- kappaB and SHH on effector genes of known importance in the skin. In addition, we will search for new target genes using new screening approaches. Second, we plan to define the role of NF-kappaB in epidermal growth control. We will characterize NF-kappaB effects on cell cycle machinery, with a special emphasis on cyclin-dependent kinase inhibitors. In addition, we plan to characterize NF-kappaB in human disease of abnormal epithelial proliferation, including squamous cell carcinoma (SCC) of the skin and its precursors. At the end of this proposed funding period, we hope to have defined the gene regulatory mechanisms involved in NF-kappaB and SHH control of epidermal growth as a basis for fundamental insights into epithelial biology and new therapeutic biology and new therapeutic targets in clinical disorders of abnormal epidermal proliferation.